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Volume 29, No 12, Dec 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 12, December 2019: 971-983

ORIGINAL ARTICLES

A complex structure of arrestin-2 bound to a G protein-coupled receptor

Wanchao Yin 1, Zhihai Li 1,2, Mingliang Jin3, Yu-Ling Yin 1,4, Parker W. de Waal 5, Kuntal Pal 5,6, Yanting Yin 1,5, Xiang Gao5,Yuanzheng He 5,7, Jing Gao1, Xiaoxi Wang1, Yan Zhang 8, Hu Zhou 1, Karsten Melcher 5, Yi Jiang1, Yao Cong3, X. Edward Zhou5,Xuekui Yu 1,2 and H. Eric Xu 1,5

1The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 3National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 4University of Chinese Academy of Sciences, Beijing 100049, China; 5Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA; 6Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India; 7Laboratory of Receptor Structure and Signaling, HIT Center for Life Science, Harbin Institute of Technology, Harbin 150001, China and 8Department of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of Medicine, Hangzhou 310058, China
 Correspondence: Yao Cong (cong@sibcb.ac.cn) or X. Edward Zhou (Edward.Zhou@vai.org) or Xuekui Yu (xkyu@simm.ac.cn) or H. Eric Xu (eric.xu@simm.ac.cn)These authors contributed equally: Wanchao Yin, Zhihai Li, Mingliang Jin, Yu-Ling Yin.

Arrestins comprise a family of signal regulators of G-protein-coupled receptors (GPCRs), which include arrestins 1 to 4. While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin, arrestins 2 and 3 (Arr2 and Arr3) are β-arrestins known to regulate many nonvisual GPCRs. The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs. Here we report the structure of Arr2 in complex with neurotensin receptor 1 (NTSR1), which reveals an overall assembly that is strikingly different from the visual arrestin–rhodopsin complex by a 90° rotation of Arr2 relative to the receptor. In this new configuration, intracellular loop 3 (ICL3) and transmembrane helix 6 (TM6) of the receptor are oriented toward the N-terminal domain of the arrestin, making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3. Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2‒NTSR1 complex. Sequence analysis and homology modeling suggest that the Arr2‒NTSR1 complex structure may provide an alternative template for modeling arrestin–GPCR interactions.


https://doi.org/10.1038/s41422-019-0256-2

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